Bupropion for smoking cessation during pregnancy

摘要 拟议的调查的目标是提供有关生物的临床前和临床信息。 安非他酮缓释(SR)作为戒烟助剂的处置、有效性和安全性 怀孕的女人。大多数吸烟并怀孕的妇女都知道已知的风险。 但由于尼古丁的成瘾性质，他们无法戒烟。行为干预有适度的， 但对戒烟有持续的、有益的效果。然而，它对吸烟量较大的人效果最差。 或者，对于非怀孕吸烟者来说，药物戒烟是安全有效的，但它们是 未被批准用于孕妇，因为其安全性和有效性尚未确定。 安非他酮SR已成功地用于非妊娠吸烟者的戒烟，其长期有效。 已显示术语安全配置文件。因此，我们提出了一项前瞻性、安慰剂对照的随机试验。 安非他酮缓释片用于妊娠期戒烟的临床研究妊娠引起的母体变化 肝酶基因的生理学和/或常见单核苷酸多态(SNPs) CYP2B6可能会改变孕期安非他酮的代谢，从而改变其在体内的浓度 母体循环，影响的是功效。此外，我们实验室最近的调查显示， 安非他酮穿过胎盘，从母体进入胎儿循环，并由组织的 酵素。此外，我们的数据还表明，胎盘代谢酶(羰基还原酶)也 作为其外流转运蛋白P-糖蛋白(P-gp)和乳腺癌耐药蛋白(BCRP)，具有 在调节胎盘中安非他酮的处置，从而调节胎儿对该药物的暴露方面起着重要作用。 这项研究的假设是安非他酮是一种安全有效的药物，可以帮助 怀孕期间戒烟。为了检查安非他酮SR的初步疗效和安全性， 将调查以下具体目标：(1)检查安非他酮SR是否减少尼古丁戒断 症状，增加戒烟率，并且与安慰剂相比具有良好的安全性；(2)确定 妊娠变化对安非他酮缓释片不同时期药代动力学的影响 同一个体的妊娠和产后；(3)确定普通单核苷酸的作用 CYP2B6基因SNPs对安非他酮和安非他酮生物转化的影响 关于怀孕7天的节制率；(4)确定慢性暴露于 安非他酮SR对胎盘羰基还原酶表达和活性的影响 安非他酮SR慢性暴露对胎盘外排转运蛋白P-gp和P-gp表达及活性的影响 BCRP。 总而言之，所获得的信息对于评估安非他酮作为潜在的治疗药物是必要的。 在怀孕期间帮助戒烟。

ABSTRACT The goal of the proposed investigations is to provide preclinical and clinical information on the bio- disposition, efficacy, and safety of bupropion sustained release (SR) as an aid for smoking cessation in pregnant women. The majority of women who are smokers and become pregnant are aware of the known risks but are unable to quit smoking due to the addictive nature of nicotine. Behavioral interventions have a modest, but consistent, beneficial effect on smoking cessation. However, it is least effective in heavier smokers. Alternatively, medications are safe and effective for smoking cessation in nonpregnant smokers, but they are not approved for pregnant patients because their safety and efficacy have not been established. Bupropion SR has been successfully used for smoking cessation in nonpregnant smokers, and its long- term safety profile has been shown. Therefore, we propose a prospective, placebo-controlled randomized clinical trial of bupropion SR for smoking cessation during pregnancy. Pregnancy-induced changes in maternal physiology and/or common single nucleotide polymorphisms (SNPs) in the gene encoding the hepatic enzyme CYP2B6 might alter the metabolism of bupropion during pregnancy and, consequently, its concentration in maternal circulation, affecting is efficacy. Moreover, recent investigations in our laboratory revealed that bupropion crosses the placenta from the maternal to the fetal circuit and is metabolized by the tissue's enzymes. Our data indicate, furthermore, that placental metabolizing enzymes (carbonyl reductases), as well as its efflux transporters P-glycoprotein (P-gp) and Breast Cancer Resistant Protein (BCRP), have an important role in regulating placental disposition of bupropion and, consequently, fetal exposure to the drug. The hypothesis for this investigation is that bupropion is a safe and effective medication that can aid in smoking cessation during pregnancy. To examine the preliminary efficacy and safety of bupropion SR, the following specific aims will be investigated: (1) Examine whether bupropion SR reduces nicotine withdrawal symptoms, increases quit rates, and has a favorable safety profile compared to placebo; (2) Determine the effect of pregnancy-induced changes on the pharmacokinetics (PK) of bupropion SR at different stages of gestation and postpartum in the same individual; (3) Determine the effect of common single nucleotide polymorphisms (SNPs) in the gene encoding CYP2B6 on its activity in the biotransformation of bupropion and on 7-day point prevalence abstinence rates in pregnancy; (4) Determine the effects of chronic exposure to bupropion SR on the expression and activity of the placental carbonyl reductases; (5) Determine the effects of chronic exposure to bupropion SR on the expression and activity of the placental efflux transporters P-gp and BCRP. In summary, The information obtained is necessary for evaluating bupropion as a potential medication for aiding in smoking cessation during pregnancy.